tbuckley/cabot-search huggingface dataset:
Dietary palmitoleic acid reprograms gut microbiota and improves biological therapy against colitis
Authors: Yiwei Chen, Qiongdan Mai, Zixu Chen, Tao Lin, Yongjie Cai, Jing Han, Ying Wang, Mudan Zhang, Shimin Tan, Zhiying Wu, Lingming Chen, Zhiyi Zhang, Yi Yang, Taimei Cui, Beiyin Ouyang, Yue Sun, Lijia Yang, Lin Xu, Sien Zhang, Jian Li, Hongbo Shen, Linna Liu, Lingchan Zeng, Shenghong Zhang, Gucheng Zeng
Journal: Gut Microbes (2023)

Magnitude and diversity of gut microbiota and metabolic systems are critical in shaping human health and diseases, but it remains largely unclear how complex metabolites may selectively regulate gut microbiota and determine health and diseases. Here, we show that failures or compromised effects of anti-TNF-α therapy in inflammatory bowel diseases (IBD) patients were correlated with intestinal dysbacteriosis with more pro-inflammatory bacteria, extensive unresolved inflammation, failed mucosal repairment, and aberrant lipid metabolism, particularly lower levels of palmitoleic acid (POA). Dietary POA repaired gut mucosal barriers, reduced inflammatory cell infiltrations and expressions of TNF-α and IL-6, and improved efficacy of anti-TNF-α therapy in both acute and chronic IBD mouse models. Ex vivo treatment with POA in cultured inflamed colon tissues derived from Crohn's disease (CD) patients reduced pro-inflammatory signaling/cytokines and conferred appreciable tissue repairment. Mechanistically, POA significantly upregulated the transcriptional signatures of cell division and biosynthetic process of Akkermansia muciniphila, selectively increased the growth and abundance of Akkermansia muciniphila in gut microbiota, and further reprogrammed the composition and structures of gut microbiota. Oral transfer of such POA-reprogrammed, but not control, gut microbiota induced better protection against colitis in anti-TNF-α mAb-treated recipient mice, and co-administration of POA with Akkermansia muciniphila showed significant synergistic protections against colitis in mice. Collectively, this work not only reveals the critical importance of POA as a polyfunctional molecular force to shape the magnitude and diversity of gut microbiota and therefore promote the intestinal homeostasis, but also implicates a new potential therapeutic strategy against intestinal or abenteric inflammatory diseases.
Dual TLR9 and PD-L1 targeting unleashes dendritic cells to induce durable antitumor immunity
Authors: Laura Fernandez-Rodriguez, Chiara Cianciaruso, Ruben Bill, Marcel P Trefny, Richard Klar, Nicole Kirchhammer, Mélanie Buchi, Julia Festag, Sven Michel, Rainer H Kohler, Elham Jones, Andre Maaske, Johannes vom Berg, Sebastian Kobold, Abhishek S Kashyap, Frank Jaschinski, Karen O Dixon, Mikael J Pittet, Alfred Zippelius
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Although immune checkpoint inhibitors have been a breakthrough in clinical oncology, these therapies fail to produce durable responses in a significant fraction of patients. This lack of long-term efficacy may be due to a poor pre-existing network linking innate and adaptive immunity. Here, we present an antisense oligonucleotide (ASO)-based strategy that dually targets toll-like receptor 9 (TLR9) and programmed cell death ligand 1 (PD-L1), aiming to overcome resistance to anti-PD-L1 monoclonal therapy. Methods We designed a high-affinity immunomodulatory IM-TLR9:PD-L1-ASO antisense oligonucleotide (hereafter, IM-T9P1-ASO) targeting mouse PD-L1 messenger RNA and activating TLR9. Then, we performed in vitro and in vivo studies to validate the IM-T9P1-ASO activity, efficacy, and biological effects in tumors and draining lymph nodes. We also performed intravital imaging to study IM-T9P1-ASO pharmacokinetics in the tumor. Results IM-T9P1-ASO therapy, unlike PD-L1 antibody therapy, results in durable antitumor responses in multiple mouse cancer models. Mechanistically, IM-T9P1-ASO activates a state of tumor-associated dendritic cells (DCs), referred to here as DC3s, which have potent antitumor potential but express the PD-L1 checkpoint. IM-T9P1-ASO has two roles: it triggers the expansion of DC3s by engaging with TLR9 and downregulates PD-L1, thereby unleashing the antitumor functions of DC3s. This dual action leads to tumor rejection by T cells. The antitumor efficacy of IM-T9P1-ASO depends on the antitumor cytokine interleukin-12 (IL-12), produced by DC3s, and Batf3 , a transcription factor required for DC development. Conclusions By simultaneously targeting TLR9 and PD-L1, IM-T9P1-ASO amplifies antitumor responses via DC activation, leading to sustained therapeutic efficacy in mice. By highlighting differences and similarities between mouse and human DCs, this study could serve to develop similar therapeutic strategies for patients with cancer.
Bispecific antibodies redirect synthetic agonistic receptor modified T cells against melanoma
Authors: Florian Märkl, Mohamed-Reda Benmebarek, Julius Keyl, Bruno L Cadilha, Martina Geiger, Clara Karches, Hannah Obeck, Melanie Schwerdtfeger, Stefanos Michaelides, Daria Briukhovetska, Sophia Stock, Jakob Jobst, Philipp Jie Müller, Lina Majed, Matthias Seifert, Anna-Kristina Klüver, Theo Lorenzini, Ruth Grünmeier, Moritz Thomas, Adrian Gottschlich, Richard Klaus, Carsten Marr, Michael von Bergwelt-Baildon, Simon Rothenfusser, Mitchell P Levesque, Markus Vincent Heppt, Stefan Endres, Christian Klein, Sebastian Kobold
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens. Methods Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo. Results MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model. Conclusion The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.
Combining histological grade, TILs, and the PD-1/PD-L1 pathway to identify immunogenic tumors and de-escalate radiotherapy in early breast cancer: a secondary analysis of a randomized clinical trial
Authors: Axel Stenmark Tullberg, Martin Sjöström, Lena Tran, Emma Niméus, Fredrika Killander, Anikó Kovács, Dan Lundstedt, Erik Holmberg, Per Karlsson
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background The implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT. Methods The SweBCG91RT trial included 1178 patients with stage I–IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. Immunohistochemical analyses of TILs, PD-1, and PD-L1 were performed. An activated immune response was defined as stromal TILs ≥10% and PD-1 and/or PD-L1 expression in ≥1% of lymphocytes. Tumors were categorized as high-risk or low-risk using assessments of histological grade and proliferation as measured by gene expression. The risk of ipsilateral breast tumor recurrence (IBTR) and benefit of RT were then analyzed with 10 years follow-up based on the integration of immune activation and tumor-intrinsic risk group. Results Among high-risk tumors, an activated immune infiltrate was associated with a reduced risk of IBTR (HR 0.34, 95% CI 0.16 to 0.73, p=0.006). The incidence of IBTR in this group was 12.1% (5.6–25.0) without RT and 4.4% (1.1–16.3) with RT. In contrast, the incidence of IBTR in the high-risk group without an activated immune infiltrate was 29.6% (21.4–40.2) without RT and 12.8% (6.6–23.9) with RT. Among low-risk tumors, no evidence of a favorable prognostic effect of an activated immune infiltrate was seen (HR 2.0, 95% CI 0.87 to 4.6, p=0.100). Conclusions Integrating histological grade and immunological biomarkers can identify tumors with aggressive characteristics but a low risk of IBTR despite a lack of RT boost and systemic therapy. Among high-risk tumors, the risk reduction of IBTR conferred by an activated immune infiltrate is comparable to treatment with RT. These findings may apply to cohorts dominated by estrogen receptor-positive tumors.
Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1–BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy
Authors: Xin Yue, Tingyu Liu, Xuecen Wang, Weijian Wu, Gesi Wen, Yang Yi, Jiaxin Wu, Ziyang Wang, Weixiang Zhan, Ruirui Wu, Yuan Meng, Zhirui Cao, Liyuan Le, Wenyan Qiu, Xiaoyue Zhang, Zhenyu Li, Yong Chen, Guohui Wan, Xianzhang Bu, Zhenwei Peng, Ran-yi Liu
Journal: Acta Pharmaceutica Sinica B (2023)

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.
Dissecting the novel abilities of aripiprazole: The generation of anti-colorectal cancer effects by targeting Gαq via HTR2B
Authors: Haowei Liu, Qiuming Huang, Yunqi Fan, Bo Li, Xuemei Liu, Changhua Hu
Journal: Acta Pharmaceutica Sinica B (2023)

Colorectal cancer (CRC) is a type of malignant tumor that seriously threatens human health and life, and its treatment has always been a difficulty and hotspot in research. Herein, this study for the first time reports that antipsychotic aripiprazole (Ari) against the proliferation of CRC cells both in vitro and in vivo, but with less damage in normal colon cells. Mechanistically, the results showed that 5-hydroxytryptamine 2B receptor (HTR2B) and its coupling protein G protein subunit alpha q (Gαq) were highly distributed in CRC cells. Ari had a strong affinity with HTR2B and inhibited HTR2B downstream signaling. Blockade of HTR2B signaling suppressed the growth of CRC cells, but HTR2B was not found to have independent anticancer activity. Interestingly, the binding of Gαq to HTR2B was decreased after Ari treatment. Knockdown of Gαq not only restricted CRC cell growth, but also directly affected the anti-CRC efficacy of Ari. Moreover, an interaction between Ari and Gαq was found in that the mutation at amino acid 190 of Gαq reduced the efficacy of Ari. Thus, these results confirm that Gαq coupled to HTR2B was a potential target of Ari in mediating CRC proliferation. Collectively, this study provides a novel effective strategy for CRC therapy and favorable evidence for promoting Ari as an anticancer agent.
Light-responsive nanomedicine for cancer immunotherapy
Authors: Weirong Kang, Yuwei Liu, Weiping Wang
Journal: Acta Pharmaceutica Sinica B (2023)

Immunotherapy emerged as a paradigm shift in cancer treatments, which can effectively inhibit cancer progression by activating the immune system. Remarkable clinical outcomes have been achieved through recent advances in cancer immunotherapy, including checkpoint blockades, adoptive cellular therapy, cancer vaccine, and tumor microenvironment modulation. However, extending the application of immunotherapy in cancer patients has been limited by the low response rate and side effects such as autoimmune toxicities. With great progress being made in nanotechnology, nanomedicine has been exploited to overcome biological barriers for drug delivery. Given the spatiotemporal control, light-responsive nanomedicine is of great interest in designing precise modality for cancer immunotherapy. Herein, we summarized current research utilizing light-responsive nanoplatforms to enhance checkpoint blockade immunotherapy, facilitate targeted delivery of cancer vaccines, activate immune cell functions, and modulate tumor microenvironment. The clinical translation potential of those designs is highlighted and challenges for the next breakthrough in cancer immunotherapy are discussed.
Cardiac toxicities in multiple myeloma: an updated and a deeper look into the effect of different medications and novel therapies
Authors: Jean El-Cheikh, Nour Moukalled, Florent Malard, Ali Bazarbachi, Mohamad Mohty
Journal: Blood Cancer Journal (2023)

With the continuous improvement in survival of cancer patients, including those with multiple myeloma, related to the novel treatment agents and therapeutic approaches, the probability for patients to develop cardiovascular disease has significantly increased, especially in elderly patients and those with additional risk factors. Multiple myeloma is indeed a disease of the elderly population and so these patients are, solely by age, at an increased risk of cardiovascular disease. Risk factors for these events can be patient-, disease- and/or therapy-related, and they have been shown to adversely impact survival. Cardiovascular events affect around 7.5% of patients with multiple myeloma and the risk for different toxicities has considerably varied across trials depending on patients' characteristics and treatment utilized. High grade cardiac toxicity has been reported with immunomodulatory drugs (odds ratio [OR] around 2), proteasome inhibitors (OR 1.67-2.68 depending on the specific agent, and generally higher with carfilzomib), as well as other agents. Cardiac arrhythmias have also been reported with various therapies and drug interaction plays a significant role in that setting. Comprehensive cardiac evaluation before, during and after various anti-myeloma therapy is recommended and the incorporation of surveillance strategies allows early detection and management resulting in improved outcomes of these patients. Multidisciplinary interaction including hematologists and cardio-oncologists is critical for optimal patient care.
Patient phenotype profiling in heart failure with preserved ejection fraction to guide therapeutic decision making. A scientific statement of the Heart Failure Association, the European Heart Rhythm Association of the European Society of Cardiology, and the European Society of Hypertension
Authors: Stefan D. Anker, Muhammad Shariq Usman, Markus S. Anker, Javed Butler, Michael Böhm, William T. Abraham, Marianna Adamo, Vijay K. Chopra, Mariantonietta Cicoira, Francesco Cosentino, Gerasimos Filippatos, Ewa A. Jankowska, Lars H. Lund, Brenda Moura, Wilfried Mullens, Burkert Pieske, Piotr Ponikowski, Jose R. Gonzalez‐Juanatey, Amina Rakisheva, Gianluigi Savarese, Petar Seferovic, John R. Teerlink, Carsten Tschöpe, Maurizio Volterrani, Stephan von Haehling, Jian Zhang, Yuhui Zhang, Johann Bauersachs, Ulf Landmesser, Shelley Zieroth, Konstantinos Tsioufis, Antoni Bayes‐Genis, Ovidiu Chioncel, Felicita Andreotti, Enrico Agabiti‐Rosei, Jose L. Merino, Marco Metra, Andrew J.S. Coats, Giuseppe M.C. Rosano
Journal: European Journal of Heart Failure (2023)

Abstract Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium–glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype‐based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence‐based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy.
Assisted vaginal births: women who tear or have a surgical cut need prompt antibiotics
Authors: Helen Saul, Brendan Deeney, Samantha Cassidy, Candace Imison, Marian Knight
Journal: BMJ (2023)

The study Humphries ABC, Linsell L, Knight M. Factors associated with infection after operative vaginal birth—a secondary analysis of a randomized controlled trial of prophylactic antibiotics for the prevention of infection following operative vaginal birth. AJOG 2023;228:328. To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/assisted-vaginal-births-women-need-prompt-antibiotics/
Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights
Authors: Stella Koutros, Lambertus A. Kiemeney, Parichoy Pal Choudhury, Roger L. Milne, Evangelina Lopez de Maturana, Yuanqing Ye, Vijai Joseph, Oscar Florez-Vargas, Lars Dyrskjøt, Jonine Figueroa, Diptavo Dutta, Graham G. Giles, Michelle A.T. Hildebrandt, Kenneth Offit, Manolis Kogevinas, Elisabete Weiderpass, Marjorie L. McCullough, Neal D. Freedman, Demetrius Albanes, Charles Kooperberg, Victoria K. Cortessis, Margaret R. Karagas, Alison Johnson, Molly R. Schwenn, Dalsu Baris, Helena Furberg, Dean F. Bajorin, Olivier Cussenot, Geraldine Cancel-Tassin, Simone Benhamou, Peter Kraft, Stefano Porru, Angela Carta, Timothy Bishop, Melissa C. Southey, Giuseppe Matullo, Tony Fletcher, Rajiv Kumar, Jack A. Taylor, Philippe Lamy, Frederik Prip, Mark Kalisz, Stephanie J. Weinstein, Jan G. Hengstler, Silvia Selinski, Mark Harland, Mark Teo, Anne E. Kiltie, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Josep Lloreta, Alan Schned, Petra Lenz, Elio Riboli, Paul Brennan, Anne Tjønneland, Thomas Otto, Daniel Ovsiannikov, Frank Volkert, Sita H. Vermeulen, Katja K. Aben, Tessel E. Galesloot, Constance Turman, Immaculata De Vivo, Edward Giovannucci, David J. Hunter, Chancellor Hohensee, Rebecca Hunt, Alpa V. Patel, Wen-Yi Huang, Gudmar Thorleifsson, Manuela Gago-Dominguez, Pilar Amiano, Klaus Golka, Mariana C. Stern, Wusheng Yan, Jia Liu, Shengchao Alfred Li, Shilpa Katta, Amy Hutchinson, Belynda Hicks, William A. Wheeler, Mark P. Purdue, Katherine A. McGlynn, Cari M. Kitahara, Christopher A. Haiman, Mark H. Greene, Thorunn Rafnar, Nilanjan Chatterjee, Stephen J. Chanock, Xifeng Wu, Francisco X. Real, Debra T. Silverman, Montserrat Garcia-Closas, Kari Stefansson, Ludmila Prokunina-Olsson, Núria Malats, Nathaniel Rothman
Journal: European Urology (2023)
The interplay between symptoms of insomnia and pain in people with osteoarthritis: A narrative review of the current evidence
Authors: Liesbet De Baets, Nils Runge, Céline Labie, Olivier Mairesse, Anneleen Malfliet, Sabine Verschueren, Dieter Van Assche, Kurt de Vlam, Frank P. Luyten, Iris Coppieters, Alberto Herrero Babiloni, Marc O. Martel, Gilles J. Lavigne, Jo Nijs
Journal: Sleep Medicine Reviews (2023)
Sanitation enzymes: Exquisite surveillance of the noncanonical nucleotide pool to safeguard the genetic blueprint
Authors: Kirsten Broderick, Mohamed Taha Moutaoufik, Khaled A. Aly, Mohan Babu
Journal: Seminars in Cancer Biology (2023)

Reactive oxygen species (ROS) are common products of normal cellular metabolism, but their elevated levels can result in nucleotide modifications. These modified or noncanonical nucleotides often integrate into nascent DNA during replication, causing lesions that trigger DNA repair mechanisms such as the mismatch repair machinery and base excision repair. Four superfamilies of sanitization enzymes can effectively hydrolyze noncanonical nucleotides from the precursor pool and eliminate their unintended incorporation into DNA. Notably, we focus on the representative MTH1 NUDIX hydrolase, whose enzymatic activity is ostensibly nonessential under normal physiological conditions. Yet, the sanitization attributes of MTH1 are more prevalent when ROS levels are abnormally high in cancer cells, rendering MTH1 an interesting target for developing anticancer treatments. We discuss multiple MTH1 inhibitory strategies that have emerged in recent years, and the potential of NUDIX hydrolases as plausible targets for the development of anticancer therapeutics.
In Vivo Stable Allogenic Cartilage Regeneration in a Goat Model Based on Immunoisolation Strategy Using Electrospun Semipermeable Membranes (Adv. Healthcare Mater. 13/2023)
Authors: Yingying Huo, Baoshuai Bai, Rui Zheng, Yuyan Sun, Yao Yu, Xin Wang, Hong Chen, Yujie Hua, Yixin Zhang, Guangdong Zhou, Xiaoyun Wang
Journal: Advanced Healthcare Materials (2023)

Allogenic Cartilage Regeneration A novel immunoisolation strategy based on a hybrid synthetic–natural electrospun semipermeable membrane is reported in article 2203084 by Yujie Hua, Yixin Zhang, Guangdong Zhou, Xiaoyun Wang, and co-workers. The immunoisolation mechanism is dependent on preventing immune cell attack by the physical barrier and blocking the negative regulatory effect mediated by destructive inflammatory factors, and thus successfully achieving stable allogenic cartilage regeneration in a goat model.